Steroid synthesis

ABSTRACT

Synthesis of steroids by cyclization of a dienyne terminating at one end of the molecule in an acetylenic group and at the other end in a cyclohexene ring wherein the olefinic group forms an allylic group with a substituent such as a thioketal or hydroxy group. Invention includes novel synthesis of the cyclization substrate, novel substrate and novel intermediates, whereby resolution of racemic mixtures and the production of d, l and dl enantiomers are made possible.

United States Patent [191 Johnson et al.

1 Sept. 9, 1975 1 1 STEROID SYNTHESIS [75] Inventors: William S.Johnson, Portola Valley,

Calif.; Ronald L. Markezich, Bloomfield, N..1.; Brian E. McCarry, EastPalo Alto, Calif.

[73] Assignee: The Board of Trustees of Leland Stanford JuniorUniversity, Stanford, Calif.

[22] Filed: Aug. 17, 1972 [21] App]. No.: 281,380

[52] US. Cl...... 260/617 R; 260/327 M; 260/340.9;

260/468 R; 260/488 R; 260/514 R; 260/586 R; 260/611 R; 260/617 E;260/648 R [51] Int. Cl. C07C 35/18 [58] Field of Search 260/617 R, 617 E[56] References Cited OTHER PUBLICATIONS Joshi et a1., Chem Abstracts,69, p. 59413q, (1968).

Prinuzry Examiner-Dona1d G. Daus Assistant Examiner-David B. Springer 57 ABSTRACT 1 Claim, No Drawings STEROID SYNTHESIS This invention relatesto the synthesis of steroids and of intermediates which are useful inthe synthesis of steroids. The invention includes novel and usefulprocesses of synthesizing such products. Among the products are noveland useful intermediates and novel and useful steroids. The inventionalso includes procedures and products which result in intermediateswhich have chiral carbon atoms and can be resolved whereby the steroidend products may be made in the desired optically active form.

Heretofore (see Johnson, Gravestock and McCarry, J. Am. Chem. Soc. 93,4332 (1971), and Johnson US. Patent application Serial No. 162,672,filed July 14, 1971, entitled Steroid Total Synthesis) it has been foundpossible and useful to produce from an ylid I and an aldehyde II aprecursor or substrate III which can be cyclized to produce a steroid IVthus.

3 I O i O P(C H C OHC o I II III

wherein R may be H or methyl and Y may be acyloxy,

etc. The five membered A ring of IV can be opened and recyclized toproduce a six membered A ring.

It is an object of the present invention to provide steroid syntheses bythe same general technique but by a more facile method and includingmethods and intermediates which make resolution possible and enable oneto synthesize a steroid having a particular optical activity accordingto choice. v

These and other objects of the invention will be apparent from theensuing description and the appended claims.

The general technique referred to above providesan ylid V and analdehyde VI and reacts them by a Wittig reaction to produce a steroidcyclization substrate VII in the following manner:

C R2 III C Z OHC V VI R3 1 C 2 III R c *9 l VII wherein R is ahydrocarbon group which is compatible with a Wittig reaction (i.e., doesnot interfere with the Wittig reaction, e.g., phenyl) and R and R arehydrogen, methyl or ethyl. Z is a cyclization initiating group whichupon cyclization under conditions sch as described in the aforesaidliterature and patent reference, affords a steroid of the generalformula VIII.

wherein R is hydrogen, methyl or ethyl derived from Z, R and R are asdefined above and R is a group derived from Z which is fused with the Bring to form the A-ring of the steroid.

We have discovered that by providing a particular class of ylid V anumber of important advantages result such as the capability of opticalresolution and the production of steroids having the desired opticalactivity, facility of synthesis and good yield. We have also discoverednovel and useful methods of synthesizing the aforesaid ylid V.

The class of ylids is typified by a thioketal having the general formulaStep 4 The ylid 5a may be synthesized as set forth in Flow Sheet 1.

FLOW SHEET NO. 1

w CO Me CO H CO Me 12 E Step3 S S OH CO Me CO Me i Step 5 i COOH Ste g P(C H 3 I -IV Ste 10 The aldehyde VI may be synthesized as described inUS. patent application cited above or it may he synthethe Johnson,Gravestock and McCarry paper and the sized as set forth in Flow SheetNo. 2 below.

FLOW SHEET NO. 2

ONa -c1 Cl \CO Et:

O z) MeOH, CH Cl P-TsOH Br 5 MeC(OMe) 3 78 F g TH 1 CH0 5&5 16 hrs H 1)LiAlH MeO C 2 Collins OHC reagent Details of preparation of and physicaldata regarding FLOW SHEET NO 3 new compounds in Flow Sheet No. l are setforth in the i' specific examples below.

The ylid 5a and the aldehyde 6 may be condensed as described inliterature and patent references cited 5 I i C 20 OHC 40 CH; l C 7 ll QThe steroid substrate 21 is an important precursor from which steroidsmay be prepared directly by cyclization of 21 or indirectly bymodification of 21 followed by cyelization of the modified product.

Flow Sheet No. 3 illustrates how 21 may be modified and the modifiedproduct converted into a steroid.

Flow Sheet No. 4 illustrates how 21 may be cyclized directly to mixturesof steroids.

form one of a pair oi resonance forms (form A) whose other form (B) hasthe capacity to combine with the Flow Sheet No.4

SnCl

GENERAL DISCUSSION OF THE STEROlD CYCLlZATlON SUBSTRATE 21 It will beseen that the steroid cyclization substrate 2] may be modified tosubstitute a kcto group for the thio ketal group before cyclization(Flow Sheet No. 3) or it may be cyclized directly (Flow Sheet No. 4). Ingeneral the cyclization initiating group associated with the acetylenicgroup R C i C (but at the opposite end ofthe dienyne chain) has thefollowing characteristics: It is a cyclohexene ring in which theolefinic group of the ring forms part of an allylic group wherein X(which is a ring substituent) is a functional group (e.g., a bivalentfunctional group such as the thioketal group S CH CH S or a monovalentgroup such as hydroxyl. The essential characteristic is an allylic groupwherein the functional substituent produces. under appropriate cyclizingconditions, a carbonium ion. at the site of the functional group toneighboring carbon of the neighboring trans olefinic group. Thismechanism is set forth below:

In C (which is the tetracylic steroid product) the dashed linerepresents a bond which provides a double ,5 bond between the C-1 and C2carbon atoms (as in 24 and 25 or where X is and remains bivalent, itconstitutes one of the bonds of the bivalent group (as in 27).

The terminal cyclohexane group is, therefore. one

having an olefinic group in the potential C-l0, Cl position of theresulting steroid which, together with a functional group in thepotential C-2 position form an allylic group capable of producing acarbonium ion in two resonance forms, one ofwhich has the positive, C+,

at the potential C positions and is, therefore, capa= ble of reactingwith the neighboring carbon of the neighboring trans olefinic group ofthe dienyn e chain to form the B-ring of the steroid product. Other examples of the functional group X include alkoxy (C, C alkoxy), acyloxy(e.g., acetoxy), halogen (Cl, Br, 1), etc. Where X is an oxygen orsulfur bearing group. anhydrous strong protonic acids such astrifluoroacetic acid, sulfonie acids (c.g.. p-toluene sulfonic acid HCl,etc. may be used. Lewis acids are also useful as shown in Flow Sheet No.4. The remainder of the cyclohexene ring may be substituted by groups(e.g., lower alkyl) that do not interfere with the cyclization reaction.

RESOLUTION OF IN'I'ERMEDIATES AND PRODUCTION OF OPTICALLY ACTlVF.

STEROIDS FROM INTERMEDIATES The natural steroids have theD-contiguration. By appropriate steps in the methods of the presentinvention it is possible to produce racemic, D- or L-steroids asdesired. Thus referring to Flow Sheet No. l. the acid 16 correspondingto the ester need not be isolated but, if an optically active endproduct is desired, it may be isolated and resolved. It will be seenthat 16 contains a chiral carbon atom at the point of attachment of thepropionic acid radical to the cyclohcxenc ring. This acid (which isproduced in the raeemic form) may be resolved by conventional techniquessuch as forming the salt of d- (or I -methyl benzylamine andcrystallization of the dor lsalt of l6 respectively.

It will be noted that the keto acid 13 also has a chiral carbon atom(the same atom as in 16) and is susceptible to enolization and the enoldoes not have a chiral carbon, therefore it tends to racemize. By usingconditions that suppress enoi txation or by reducing the keto group of13 to hydroxyl and protecting the hydroxyl as by methylation. resolutionat this stage can be effected.

in the following examples, except where otherwise stated, all compoundshaving chiral carbon atoms were prepared in the dl form. The sameprocedures apply to preparation of optically active forms providedresolution is accomplished at a suitable stage. 3

Example 1:

3-Methyl- 4-methylene-cyclohex-2-enonc l l To 243 g (1.08 mole) of crudeethyl 3-methylcyclohex-3-enone-4 carboxylate ethylene kctal (A) in (100ml of dry tetrahydrofuran contained in a 3-litcr flask fitted with amechanical stirrer, nitrogen inlet. and addition funnel was added slowly(with ice-bath cooling) over a 3 hour period 400 ml ofRed-Al solution(Aldrich Chemical Co., 2.78 moles of hydride) in 200 ml of drytetrahydrofuran. After the addition was complete the reaction mixturewas allowed to stir overnight at room temperature. Excess Red-Al wasdestroyed by.

the addition of 10% aqueous sodium hydroxide and the precipitatedaluminum salts were filtered off through eelite. To the organic filtratecontaining 3- methylcyclohex-3-enone-4-hydroxylmethyl ethyleneketal wasadded 1000 ml of 10% aqueous hydrochloric acid and this mixture stirred(mechanical stirrer) at room temperature under nitrogen for 4 hours. Thereaction mixture was poured into a separatory funnel and extracted withether (3 X 1000 ml). The ether extracts were washed with saturatedsodium bicarbonate solution, saturated sodium chloride solution and thedried ov er anhydrous sodium sulfate. Filtration and concen- Example 2:

Methyl-2carbomethoxy-3-( 2-mcthyl-4-oxo-2- cyclohexene )propionatc l2)Into a 2-liter round-bottom flask equipped with a nitrogen inlet,magnetic stirrer, and addition funnel was placed 900 ml of methanol and3.828 g (0.07 mol, Matheson, Coleman, and Bell) of sodium methoxidc.After stirring for 15 minutes, 395 g (3 moles) of dimethyl malonate wasadded and this mixture stirred for minutes. Then was added dropwise 1 10g (0.9 mole) of 11 in 100 ml of methanol. The reaction mixture turnedgreen which faded to a dark yellow. After stirring at room temperaturefor l9 hours (vpc of a aliquot showed no dienone remaining) the solutionwas poured into 2 liters of water and acidified to pH 1 with 10% aqueoushydrochloric acid. The diester was extracted Example 3:

Methyl-3-( 2-methyl-4-oxo-2-cyclohexene )-propionate l4) lnto a mlround-bottom flask equipped with a reflux condenser, magnetic stirrer,oil bath. and nitrogen inlet was placed 2().335 g of at ca. 45/55mixture of 12 (ca. 9.02 g, 35.5 .mmole) and dimethyl malonate (ca. 11.3l g). 25 ml of glacial acetic acid, 25 ml of water, and 5 ml ofconcentrated hydrochloric acid. This mixture was refluxed for 19 hours,cooled. and extracted with dichloromethane (3 X 100ml). The organicextracts were washed with saturated sodium chloride solution and driedover anhydrous sodium sulfate. Filtration and evaporation in vacuoafforded 8.109 g of a brown oil. The crude acid was esterified accordingto the procedure ofClinton and Laskowski. Into a 100 ml round-bottomflask was placed the crude acid, 30 ml of dichloromethane. 12 ml (0.3mole) of methanol. and 0.1 g of p-tolnenesulfonic acid. The mixture wasrefluxed for 17 hours, and then the cooled reaction mixture was washedwith water, saturated sodium bicarbonate solution, and saturated sodiumchloride solution, and dried over anhydrous sodium sulfate. Filtrationand concentration in vacuo afforded 5.685 g of a brown liquid.Distillation afforded 4.010 g (58% yield) of a light yellow liquid. bp 115l 18/0.15 mm.

Anal. Calcd for C H O C. 67.32;. H.-8.22;.Found:

C.67.38 /('.H,8.19 /1 i; 1

\"pc 39? XE-60/l72 4 min. 97%

3 min. 2%

2 min. 171 1 1R (film):6.00,a(CO). 5,.76u(C=O) NMR (CDCM): 62.00 (3H5).3.67 (3H5). 5.80

( 1H.S) i

Example 4: Methyl 3-( 2-methyl-4-oxo-2-eyclohexene )pr.opion at eethylene thioketal 15) i A. Into a 250 ml round-bottom flask fitted witha magnetic stirrer and drying tube was placed 6.027 .g (30.8 mmole) of14. 100 ml of chloroform and ml of ethanedithiol followed by theaddition of 2 ml of boron tritluoride etherate/The solution turnedyellow and water started to separate. After stirring at room temperaturefor 5.5 hours the reaction mixture was poured into 200 ml of waterfollowed by 300 ml of ether. The two layers were separated and theorganic portion washed with 10% aqueous sodium hydroxide 2 X 100 ml).saturated sodium chloride solution 1 X200 ml). and dried over anhydroussodium sulfate. Filtra tion and concentration in vacuo afforded 8.235 gof a ellow-orange liquid. Bullrto-bulb distillation at 180/0.025 mmafforded 7.949 g (95%yicld-l of the,thi okctal as a light yellow liquid.

B. Into a 2-liter. roundbottom flask fitted with a reflux condenser.magnetic stirrer. heating mantle. and nitrogen inlet was placed 463 g ofa ca. 45/55 mixture of 14 ca. (208 g. 0.82 mole) and dimethyl malonatcca. (255 g). 500ml of glacial acetic acid. 500 ml of water. and 100 mlof concentrated hydrochloric acid. The mixture was refluxed for 22hours. cooled. and poured into 2 liters of water. The acid was extractedwith three-1000 ml portions of dichloromethane. theorganic extractswashed with saturated sodium chloride solution and concentrated in vacuoto 1000'm1.' The crude acid was esterified according to the procedure ofClinton and Laskowski. Into a 21iter round-bottom flask was placed thedichloromethane solution of the acid. 360 ml of methanol (9 moles). and3 g of p-toluenesulfonic acid. This mixture was refluxed for 21 hours.and then the cooled reaction mixture was washed with water. saturatedsodium bicarbonate solution. and saturated sodium chloride solution. Thedi-,

chloromcthane solution containing the keto-esterwas placed into a2-liter round-bottom flask followed by.

200 ml of ethanedithiol. The flask was fitted with a dry.-

ing tube and magnetic stirrer and 40 ml of boron trifluoride etheratewas added. The solution was stirred over night 15 hours) and then pouredinto a scpar atory'fun vacuo afforded 197 g of brown liquid.Distillation-afa 5.5 min. 99%

1R (film): 5.73 c=0 NMR cnctazarw (3H.S);*3;33 (4H3). 3.68

Example -5:3-( 2-methyl4-oxo 2-cyelohexene )-propionic acid ethylenethioke'tal 16) into a 500 ml round-bottom flask equipped with a magneticstirrer and nitrogen inlet was placed 56.1 (0.206 mole) of 14. 300 ml ofmethanol. and 19.7 g. (0.30mole) Ofi85'7r. potassium hydroxide in 75 mlof water. After stirring at-room temperature for 24 hours the mixturewas poured into a separatory funnel followed by 400 ml of water. Themixture was extracted with 200 ml of ether and the aqueous solutionacidified to pH 1 with 10% aqueous hydrochloric acid. The acid wasextracted with three-300 -ml portions of dichlo'romethane. After washingwith saturated sodium chloride and drying over anhydrous sodium sulfate.filtration and concentration in vacuo afforded 53.7 g (100% yield) ofthe acid as thick light-brown oil.

Anal. CLllCtl for 0. 11. 5... c. x1; H. 7.02; 5. 24.78; Found: C. 55.90;H. 7.02; S. 24.91

NMR (CDCl ):51.71

(1H.S). 11.22 lH.S)

was). 3.33 (tins-x51);

Example 6: Resolutionof tlhe Acid 16 into dand l-Salts To a solution of53.2 g (0.206 mole) of d.l-acid 16 in 90.0 ml of hot ethyl acetatecontained in a lliter Erlenmcyer flask was added 25.157 g (0.207 mole)of d-a-methylbenzylaminc in 100 ml-of hot ethyl acetate. The resultingsolution was heated to boiling for a few minutes and then allowed tocool. A seed crystal was added and the solution cooled slowly to roomtempera ture. Filtration afforded 315 g (0.083 mole. 409?) of light tanneedles [(2 1,, free acid 10.1 Another recrystallization from 400 ml ofhot ethyl acetate. cooling slowly" to room temperature. afforded 24.8 g(0.065 mole) of needles {ul of free acid 13.1". One morerecrystallization from 340 ml of hot ethyl acetate gave 20.5 g (0.054-mole. 26%) of white needles. mp 107113, [01],, of free acid 13.7". 1

Anal. Calcd for cg H No s C. 63.31; H. 7.70; N. 3.69; S. 16.87; Found:C. 63.42; H. 7.63; N. 3.73; S. 16.88

The mother liquor from the first recrystallization was concentrated to700 ml and cooled to 0. Cotton-like crystals separated which are thesalt from the l-acid. These were not collected but this mixture wastreated with 10'/( aqueous hydrochloric acid to liberate the free acid.To a solution of ca. 32 g (0.123 mole) of 1- enriched acid 1-16 in 400m1 of hot ethyl acetate was added 15.30 g (0.126 mole) of1-u-methylbenzylamine in 100 ml of hot ethyl acetate. The resultingsolution was heated to boiling for a few minutes and then allowed tocool slowly to room temperature. Filtration afforded 29 g (0.076 mole,3771) of off-white needles,

forded-92.4 g (0.34 mole. 41% yield) of the thioketak ester 15 as aclear liqiid. liquid. 173 l74/0.1;5 mm;,=

Anal. Calcd for C H O S C. 57.34 ;;H. .7.40S.

23.50; Found: C. 57.22; H. 7.28; S. 23.57

VpC 3% XE-/l90 4 min. 1%

. (1],, of free acid 8. 15. Another recrystallization from from 320ml ofhot ethyl acetate gave 16.2 g (0.043

mole. 21%) of.offwhite needles. mp 107-l12, [01],, of free acid l4;2

To 19.762 g (0.052 mole of salt d-l7 suspended in 300 ml of ethylacetate was added 200 ml of 107; aqueous hydrochloric acid. This mixturewas stirred for .10 minutes and then poured into a separatory funnel andseparated. The organic layer was washed with brine and dried overanhydrous sodiumsulfate. Filtration and evaporation in vacuo afforded13.904 g 104% yield) of the acid d-l6 as a light tan oil lalr, 13.7".

Bulb-to-bulb distillation. l69l73/0.0l5 mm afforded an analytical sampleas a clear oil.

Anal. Calcd for C H O S C. 55.81; H. 7.02; 5. 24.78: Found: C. 55.94; H.7.12: S. 24.89.

Example 8: 3-(2-methyl-4-oxo-2-cyclohexene)-propyl alcohol ethylenethioketal 17) The thioketal methyl ester l5 35.74 g 131 mmoles).was-dissolved in 300 ml dry THF in an ovendried 1 liter llask equippedwith a magnetic stirring bar. addition funnel and an N inlet. Thesolution was cooled to 0 and 50 ml (340 mmoles H" l of Redal. (sodiumbis-( Z-methoxyethoxy) aluminum hydride in benzene) diluted with 60mldry THF was added from the funnel over minutes. The solution was stirredfor 4 hours at 0. After this time the reaction mixture was carefullyquenched with 59? aqueous sodium hydroxide by dropwise addition until agranular precipitate was obtained. The almost clear supernatant wasdecanted and the aluminum salts were washed with ether. The organicsolvent was evaporated in vacuo and the residue was taken up'in ether.The ether solution was extracted with water (2 X 500 ml) and the aqueouslayer were extracted with ether (2 X 200 ml). The combined ether layerswere washed with saturated brine and then dried over anhydrous potassiumcarbonate. Evaporation of the solvent in vacuo left 32.2 g pale yellowoil 131 mmoles. quantitative recovery) of the thioketal alcohol (17). Asample was purified by the silica gel (ethyl acetate) R 0.48. anddistillation bp l80/0.050

Example 9: 3-( 2-methyl-4-oxo-2cyclohexane )-propanol tosylate ethylenethioketal l8) In an oven-dried 250 ml flask was plaeedptoluencsulfonylchloride (recrystallized from hexane/- chloroform; 36 g 0. 1 88, mole.1.42 equivalents) and 50 g ml dry pyridine. The mixture was stirred andcooled in an ice water bath. Then the above crude thioketal alcohol 17)was dissolved in 30 ml dry pyridine and added slowly to the chilledtosyl chloride/pyridine mixture. Transfer of the alcohol was completedwith two pyridine washings 15 ml then 5 ml). Soon after the alcoholsolution had been added the mixture became a very pale yellow. clearsolution but within five minutes a fine white precipitate of pyridiniumhydrochloride began to come out ofsolution. After stirring two hours at0 8 ml of lactic acid 75 mmoles) was added dropwise via syringe. Afterstirring an additional 30 minutes at 0 the reaction mixture was pouredinto 1 liter of 10% HCl overlaid with other (500 ml). The ether layerwas extracted with another liter of 10% HCl. The combined aqueouslayers'were then extracted with ether (2 X 200 .mil). The etherlayerswere washed successively with H O. saturated N'aHCO,, andsaturated brine. After dry ing over anhydrous potassium carbonate thesolvent was evaporated in vacuo leaving the thioketal tosylate (18) 'avery .pale yellow viscous oil. 48.6 g (126.5 mmoles. 96% yield). Thisproduct was used directly in the next step. A sample of the tosylate 18)was purified by chromatography on Florisil with 107: ether in hexane.

Analysis: Calcd for'C H S O C. FoundLC. 57:17;- H. 6.54

Spectral Data: I

ring

IR: (CHCL, soln) 3.41-(CH) 7.36. 8.40. 8.51.(tos \late bands) -|01],,18.5" (.CHCL.)

a 18.6" (CHCL-ll tlc: Ego/hexane (Z/l) R ,-().54

' v Example 10: l -lodo- 3 2-methyl-4-oxo-2-cyclohexene )-propaneethylene thioketal l9) Excess sodium iodide was added to 180 ml acetoneand stirred at 23- for 30 minutes before the flask was set aside andallowed to settle and cool to room temperature. This sodium iodidesaturated acetone was added to the above crude thiokctal tosylate (l8)and stirred at 23". Then 0.5 ml of diisopropylethylaminc was added tothe stirred suspension to prevent isomerization of the olefinic bond.After 2 hours half of the acetone wasevaporated in vacuo before thereaction mixture was poured into 1 liter of water overlaid with 500 mlether. The aqueous layer was extracted with ether (2 X 200 ml). Thecombined ether layers were washed with saturated sodium bicarbonate andsaturated brine. After drying over anhydrous potassium carbonate thesolvent was evaporated in vacuo to yield the thioketal iodide 19). apale yellow viscous oil. 41.9 g. The crude iodide was applied to 250 gof -200 mesh Florisil and eluted with 5% ether in hexane; 39.45 g (0.112moles. 89% yield) of clear colorless oil was collected. This representedan overall conversion of 85.5% from the thioketal ester l5 Analysis:Calcd for: C H I: C. 40.69; H. 5.41; l. 35.83 Found: C. 41.18; H, 5.39;l, 35.75 Spectral Data:

1R: (liquid film) 3.41 (CH) 6.09 c C 7.89. 8.19. 8.60. 11.80 tlc: EtO/hexane (2/1) R 0.70 [01],, 24.1

Example 11: 3-( 2-methyl4-oxo2cyclohexcne )-propancltriphenylphosphonium iodide ethylene thioketal In a 100 ml flask wereplaced 12.3 g (34.8 mmol) of the thioketal iodide (19). 12.8 gtriphenylphosphine 1.4 equivalents) and 15 ml dry acetonitrile(distilled from CaH All three components were necessary to effectcomplete solution at 50. Huenigs base (diiso propylethylamine 1.0 ml)was added and the reaction vessel was flushed with dry N and then placedin a 50 oil hath. After 18 hours the homogeneous reaction mixture wasdiluted with ml dry methylene chloride then poured into swirling hexane(250 ml). A'yellowwhite gummy product separated from the hexanesolution. After a little swirling the supernatant was decanted and thegummy product washed with hexane (2 X 30 ml). The hexane washings madethe product gummier and far less mobile. Excess solvents were removed byaspirator. The crude product swelled to give a solid foam (volume about600 ml) which when dry was broken down to a powder with a spatula. Afterthe bulk of the volatiles were removed by aspirator the product wasdried in vacuo then placed in a drying pistol at 68 (hexane) /0.010 mmto yield an ivory white powder 20.5 g (33.3 mmoles, 96% yield).

IR: (CHCL, soln) 3.40 (CH) 6.31 (aromatic CH) 1 8.32. 9.02, 14.05 (allstrong) d 889() [(1 1f 4.79(CHCl [11],, 508 (CHCl;,)

Example 12: 7-methyl-13-(2-methyl-4-oxo-2-cyclohexcne)-tridecatrans.trans-6.l0-dien-2yne ethylene thioketal (21 In an oven-dried 250 mlflask equipped with a magnetie stirring bar was placed 1.5.92 g (25.9mmoles) of the phosphonium salt (20). After flushing the flask with drynitrogen, 50 m1 of dry THF were added. The partially dissolveed salt wasstirred at 23 as phenyllithium in THF was added via syringe untili apermanent yellow was obtained (indicating a small concentration of thephosphorous ylid 5a).

The phenyllithium was prepared by the procedure of Gilman (H. Gilman, R.G. Jones. Organic Reactions V1, p. 352). When the dark filtered solutionof the phenyllithium in ether was placed in a freezer at 17, thephenyllithium was observed to crystallize in large white crystals. Thesupernatant ether was decanted and dry THF was added. Theconcentrationof phenyllithium was determined by the method of Watson andEastham (J. Organomct. Chem., 9 165( 1967)). which uses1.10-phenanthroline (Aldrich) as a carbon base indicator. Solutions ofphenyllithium in THF when stored at freezer temperatures (15 to 20) arestable and hold their titer within 571 for two months or longer.

After the permanent yellow color was obtained 1.00 equivalents ofphenyllithium in THF 1.69 M. 15.3 ml. 259 mmoles) was added causing thetemperature of the mixture to rise. Complete dissolution to a clearcherry red solution occurred within a minute. The solution of the ylid(5a) was cooled to in a dry iceacetone bath. After stirring 15 minutesat 70 the al dehyde 6 (4.25 g. 25.9 mmole) in 5 ml dry THF was addeddropwise via syringe. The color of thesolution lightened to a paleorange as the solution was stirred for 15 minutes. Then 20 ml ofphenyllithium in THF 1.3 equivalents) was added via syringe generating avery dark red solution of the 'betaine ylid. Sufficient dry ether (ml)was then added to adjust the THF/ether ratio to 1/ l. The temperaturewas allowed to rise to 30. After stirring l0 1 5 minutes at 30 the ylidwas quenched with methanol togive a pale tan mixture which was allowedto warm to 23 and stand overnight.

The reaction mixture was added to 600 ml hexane and after stirring a fewminutes the precipitated triphenylphosphine oxide was allowed to settleand the slightly cloudy supernatant decantedThe precipitated oxide waswashed with ml hexane. The solvent was evaporated in vacuo leaving eayellow oil. The crude product was applied to a 100 g column of Florisil(100-200 mesh) and eluted with hexane (to remove most of the biphenyl)followed by 5% ether in hexane. A'total of 6.917 g of thioket'al '(21was collected 18.5 mmoles. 71 .57: yield). Vpc analysis shows less than2% of the ply-unsaturated isomer and about 171 cis olefin. A sample waspurified by the silica gel (benzene) R 0.55 and distillation bp /25 1.

ea a 1 2 3.31 (s, 4H. thioketal) 5.41 (m. 2H, e \f\e H 5.60 (s, 1H,vinyl H in ring) 1R: (CHCL, sol'n) 3.32 p.. 3.41. 3.49 (CH) 10.321m.trans Mass spectrum (Atlas) M 28 (thioketal cleavage) tlc:

Ether/hexane 1/1) R, 0.65 benzene R 0.57

lal v l9.7 lal,, =+2l.0 I For cyclization of 21 to occur to afford asteroid. it is necessary that both olefinic groups of the. dienynesegment be trans groups. The trans group of the a1dehydc 6 is assured byits method of synthesis.The trans character of the olefinic groups whichforms the C-8 and C-9 portions of the steroid is assured by its methodof synthesis above described whichincludes steps.

which will be recognized as the Schlosser modification of the Wittigsynthesis; see Schlosser, Angewandte Chemie, International Edition, 5,p. 126 1966).

' Example 13: 7-Methyll 3( Z-methyl-4-oxo-2-cyclohexene )-tridecatrans,trans-6,10-dien-2-yne 22 In a 250 ml flask equipped with magneticstirrer were placed 4.749 g of the thioketal 21 (12.7 mmole), 160 mlacetonitrile. 32 ml H and 18 ml methyl iodide. This solution was stirredunder an atmosphere of dry nitrogen at 45 for 1 1 hours. When an aliquotwas re-' moved and analyzed by vpc. the hydrolysis was found to becomplete. The reaction mixture was poured into 350 ml ether and washedwith dilute N33520:) (2 X400 ml). After extraction of the aqueous layerswith either the usual work-up was followed. This left a yellow oil whichwas chromatographed on 100 g. 100-200 mesh Florisil. The column waseluted with hexane followed by hexane containing ether then 20% ether. Atotal of 3249 g of the a,B-unsaturated ketone (22) was obtained (10.9mmoles. 86% yield). An analytical sample was prepared by. treatment withRaney nickel in ethyl acetate/ethanol for one-half hour followedbyevaporative distillation at 160/25 Analysis: Calc'd for C H O: C, 84.51:H, 10.13; Found: d1: C. 84.61; H, 10.34

Spectral Data:

NMR: (CDCI -Y- 1.585 (s, 3H. vinyl CH I 1.73 (s, 3H. C C-Cfl;,)

1.93 (s. 3H, vinyl C ll;, of ketone) 5.41 (m 2H s e H 5.80 (s. 1H, vinylH of ketone) 1R: (CHCl soln) 3.32 a, 3.41, 3.4) (CH) (1.02 7.24. 7.99

10.32 (trans 1 1.65

Example 13A: Modified Hydrolysis of Thioketal 21 The method of Example13 causes enolization of the ketone 22. thereforeracemizes the thioketal21 if that compound is used in resolved, optically active form. Theprocedure of ,this present example avoids or represses enolization andresults in an optically active ketone 22.

Into a 10 ml round-bottom flask was placed 58 mg (0.155 mmole) ofl-thioketal 21 from acid with [a],, l0.1), 5 m1 of dimethylformamide,350,121 (800 mg, 5.6 mmole) of methyl iodide, 1 ml of water, and 26 mg(0.26 mmole) of calcium carbonate. This mixture was stirred at roomtemperature for 42 hours. Vpc of an aliquot on 3% XE-60 /225 showedketone 22 (76%, R, 5 min), 6% of unreacted thioketal (R, 13 min), and19% of an unknown compound at R, 17 min. The reaction mixture was pouredinto a separatory funnel followed by ether. The mixture was washed withbrine (pH of aqueous portion is 34) and dried over anhydrous sodiumsulfate. Filtration and evaporation in vacuo afforded 52 mg of a yellowoil. This material was adsorbed onto a silica gel plate 10 cm X 20 cm X0.1 cm) and eluted with ethyl acetate: benzene 1:4) to afford 24 mg (52%yield) of the ketone 22 as a clear oil, [(Xll) 4l .0

Example 14: 7-Methyl-13-(2-methyl-4-hydroxy-2-cyclohexenc)trideca-trans, trans-6,10-dien-2-yne (23) In an oven driedm1 flask equipped with a magnetic stirrer bar were placed 2.158 g (7.24mmoles) of the unsaturated ketone (22) and 25 ml dry THF. This solution.was stirred under dry nitrogen and cooled to 0. A solution of 0.8 m1Redal in 5 ml dry THF (1.5 equivalents of H was added slowly via syringeto the chilled solution of ketone (22). The nearly colorless solutionwas stirred for 1 hour at 0. After this time the excess Redal wascarefully destroyed with 5% aqueous sodium hydroxide until a granularprecipitate was formed. The almost clear supernatant was decanted andthe salts washed with ether. The usual workup yielded the allylicalcohol (23), a very pale yellow oil, 2. 128 g (99% yield). There was nounreacted ketone by infrared spectroscopy. A sample of the crude productwas purified by chromatography on No. 5 basic alumina (Woelm) with 20%ether in hexane as eluent. The last traces of solvent were removed at23/ 10p Analysis: Calcd for C H;, O: C, 83.94; H, 10.73; Found: dl: C,84.00; H. 10.46 Spectral data:

'lR:(liq. film) 3.00 (OH); 3.41, 3.49 (CH); 6.04 (C =C), 7.26, 9.65,10.32

Example 15:

In an oven-dried 500 ml 3-necked flask equipped with a serum cap. astopcock adapter, magnetic stirrer A-pregnen-20-one bar and a dryice/acetone condenser was placed 2.50:.

g (8.33 mmoles) of the allylic 1 1 01101 2 3' Then 250. I ml of 1.1difluoroethane (Matheson Gas, Gentron .152. r

80% of the ethylene carbonate and most of the sub-3 strate dissolved.Then 20 ml of trifluoroaeetic acid (8% by volume) was introduceddropwise via syringe to the stirred. refluxing (25) mixture. A pinkishcolor began to develop after 25% of the acid had been added.

After 15 minutes the solution had become lighttan in'- color andcompletely homogeneous. The reaction was quenched after 1 /2 hours bythe slow addition of 1071 K CO in 50% aqueous methanol. Once quenchedthe reaction mixture was diluted carefully with 100 m1 ether followed byanother 100 ml of the 10% K CQ, so-

lution. The difluoroethane was allowed to boil away and the reaction wasstirred overnight. The reaction was poured into water (200 ml extractedwith ether (3 X 100 ml) and finally worked up as usual. Evaporation ofthe solvent in vacuo left 2.614 g of crude 13 pregnanone (24) as a paleyellow oil a/,B ratioat C-17 85/15). The crude material wasapplied to 50g of l00200 mesh Florisil. Elution with 250 ml of hexane afforded 232 mgof non-polar materialsfThe desired tetracyclic ketone (24) was elutedwith 1.5 /1. then 3 and 47! ether in hexane. A total of 1.620 g ofketone (24) was recovered for a-yield of 65%. One of the fractions wasrecrystallized from ethyl acetate in methanol to give white plates mpl01103. that rearranged into needles mp 1 13] 14.5. Furtherrecrystallization give white mp 102.5-l03.5. From another cy-' clizationwhite needles mp ll4.5" -1l7.5 were obtained. When these crystals weredried at 68/20 a a small amount was observed to sublime and collect on acold part of the apparatus, mp "1 19-120. Howeve,r when the bulk wassublimed at l25/25p. two forms were observed; mp 101.5l02.5and 111'l 12.All. recrystallized samples are pure B-isomer at C-17.

Analysis: Calcd for C. ,H;, O: C.. 83.94;H. 10.73!

Found: dl: C. 84.05; H.

10.99; 1-c. 83.96; 11. 10.81 Spectral Data: i

Cyclization ofThiolketal 21 withtstannic Chlon'de lnto a ml round-bottom'blask'fitted with a' rubber serum cap and a magnetic stirrer was placed247 mg (0.66 mmole) of thioketal (21) (optically active. from acid (14)with la],, "-l0.l) and 20 ml of dry dichloromethane. This mixture wascooledto'O with anice bath and 0.5 ml (4.37 mmole, 6.6 eq of stannicchloride was injected slowly. The first drop of acid turned the solutionyellow which turned orange with additional acid. This orange solutionwas stirred for 15 minutes at 0 and then poured into aqueous 10%hydrochloric acid and extracted with ether. The ether extracts werewashed with'saturated sodium bicarbonate solution. brine and dried overanhydrous sodium sulfate. Concentration in vacuo afforded 243 mg yieldof a vinyl sulfide mixture of the chlorocarbons (25) and (26) as a whitesemi-solid.

The nmr spectrum showed singlets at 8 0.87, 0.92. and 1.03 and a vinylproton at 5 5.6.

Example 17 Cyelization of Thioketal 21 with Titanium Tetrau chloridelnto a 50 ml round-bottom flask fitted with a magnetic stirrer andnitrogen inlet was placed 278 mg (0.744 mmole) of thioketal (23) and 20ml of dry 1,2- dichloroethane. Cooled to 30 in an acetone/dry ice bathand 0.5 ml (4.5 mmole. freq) of titanium tetrachloride was injectedslowly. The first drop turned the solution orange which turned red andthen deep purple with additional acid. This dark purple solution wasstirred for 10 minutes at 3 0 to -25 and then poured into 75 ml of 10%aqueous hydrochloric acid and extracted with ether. The ether extractswere washed with saturated sodium bicarbonate solution, brine and driedover anhydrous sodium sulfate. Filtration and concentration in vacuoafforded 295 mg of a light yellow oil. This material was absorbed onto asilica gel plate (20 cm X 20 cm X 0.1 cm) and eluted with ethylacetate:- hexane 1:4) to afford 242 mg (79% yield) of a clear oil whichsolidified on standing. Vpc on 3% XE- 60/240 showed 4 peaks; 7071 ofcompound (27) (R, 12.25 min), 1271 of compound (28) (R, 14.25 min) andtwo other components of unknown structures. 15% (R, 8.5 min) and 371 (R,10.75 min). Recrystallization from hexane afforded white needles. mp l58, vpc of this material. showed only the peaks corresponding to (27)and (28) in the same ratio as above.

NMR (CDCL l: 8 0.83.(S),

53.19 (S) Mass Spec. (Atlas): M+ 410 60.89 (s); 132.14. and

Example 18 A -ZO-chlorapregnadiene (29) and A, A"-""' 17-D-.homopregnadier1e (30) 1n a 50 ml flask equipped with a magneticstirrer bar were placed 0.150 g (0.50 mmoles) of the allylic alcohol(23) and 15 ml dry methylene chloride. This solu tion was chilled to-30'in a dry ice/acetone bath. The reaction mixture was stirred as 0.175ml stannic chloride (3.0 equivalents) were added dropwise via syringe. Astrong orange color developed after 1 equivalent of stannic chloride hadbeen added. The cloudy orange solution was stirred at -20 to 30 for 75minutes be- 'fore 7 ml of dry ether was added followed by a slightrecovered forfa 7071 yield. Vpc. analysis-(3% OV.'17. 205) showed asingle peak (RT min, l 1.4% )and a:

doublet (RT l6 and 18 min, 88.6% Ratio 62/38). The I above oil wasrecrystallized from hot absolute. ethanol affording fine plates mp100406. Vpc analysis of: these crystals showed only the doublet of peakin the ratio 6l'/39.

In another experimcnt 36l mg of the allylic alcohol- (23) was cyclizedin -36 ml of l,l-dichloroethylene (freshly distilled from -K. ,CO andhydroquinone The above solution was chilled to. to and the temperaturewas maintained in that range from 50 minutes after 0.35 ml stannicchloride (2.5 equivalents) had been added. This reaction was quenchedwith pyridine and worked up as previously described. Chromatography onFlorisil with hexane yielded 246 mg of a clear colorless oil (64.571yield Vpc showed the same single peak l6.471-) and the same doublet;however the ratio of these two peaks was 85/15. Two.recrystallizationsfrom absolute ethanolyiclded 92 mg of white plates mp l06l09 (Ratio88/12). lt was subsequently shown that the doublet peaks are thetetracyclic-chlorocarbons (29 and 30), the 'one with the shorter vpcretention time having a S-mcmbered D ring 29).

Analysis: Calc'd for C- H,-, 7l:: 79.00,; H. 9.80; Found: C. 79.24; H,9.56 I Spectral Data:

IR: (CHCL, soln) 3.4lp. 3.49 (CH) 9.18, 9.97. 10.43. 11.97 tlc: 20-ethylacetate/hexane R, 0.63

i Example 19 Degradation of Vinyl Sulfides (25) and (26) into 5androstanl 7-one (3 l) i The vinyl sulfide mixture 25/26 produced as inExample l5 is very difficult to separate. To separate the steroid (25from the D-'homo steroid (26). the mixture was subjected toa series ofsteps as follows:

a. Treatment 25/26 with Raney nickel. lnto-a 25 ml round-bottom flaskwas placed l90 mg'(0.464 'mmole if pure) of the above vinyl sulfidemixture 25/26. 10 ml of ethyl acetate, 5 ml of acetone and l'.-l39 g' ofwet (water) Raney nickel. The mixture was stirred at room temperaturefor minutes and then refluxed for 30 minutes, cooledand filtered toafford a clear oil which by nmr still contained vinyl. sulfide. This oilwas retreated under the above conditions except that the'mixture wasrefluxed for 2 hours. cooled, filtered toremove Raney nickel, the nickelwashed' several times with ethyl acetate. The organic washings werewashed with brine and dried over anhydrous sodium sulfate. Filtrationand-evaporation invacuo afforded I41 mg (927v-yieltl)iof the olefins32/33. The vpc on 3% XE 60/188" showed four small peaks with R, 4minutes" and 55% 26 (R,= 7 minutes) 32 27 (R,= 8 minutes). i and twoother components of unknown structures, l2?! "androstan-l 7-one (3l),(al 48.5. Vpc on 3% XE- (R) 4.5 minutes) and 2% (R,'= 6.25 minutes).This material ifoinjected'with chloro olefin prepared as in Example 15.v

b. Hydrogenation. The above olefins 32/33 136- mg) were hydrogenatedover ca. mg of 10% Pd/C in 10 ml of -ethylacetate for 6 hours at roomtemperature. Filtration and evaporation of the solvent in vac uoafforded l l8 mg (87%) of the chlorocarbons 34/35.

c. Ozonolysis. Chlorohydrocarbons'34/35 (118 mg were dissolved in amixture of 1 ml of methanol and 2 ml'of ethylacetate and the solutionchilled to 78. Ozone was bubbledthrough the solution until a permanentblue color was produced. The solution was allowed to stand for 5 minutesand the excess ozone was flushed from the solution with oxygen.Dim'ethylsulfide (0.5 ml) was then added at 78 with stirring and thesolutionstirred while warming to room temperature. After 30 minutes thesolution was concentrated in vacuo to afford l 34 mg of a yellow oil.Vpc on 371 XE- 60/225 showed apeak at R, l.25 minutes 13% 5,8-androstan-l7 one (3 l at R, l.5 minutes the keto-ester (36) at R, 5.75minutes (26%) and a peak at R, 9 minutes (6% This material was absorbedeluted with ethyl acetate: hexane (1:4) to afford 3 bands. R, 0.62,0.42. and 0.27. The fastest moving band contained 22 mg of an oilcontaining four components by vpc whichhad .no carbonyls in theinfrared.

The slowest moving band contained 15 mg (11% yield) of the keto-estcr(36). Vpc on 3% XE-/225 showedone peak at R, 5.75 minutes. This materialwas'distillcd bulb-to-bulb at l50/0.02 mm to give a clear oil.

Analysis: Calc'd for C H O C,'75.82' H, 10.4 l3.77; Found: C, 75.54; H,l0.05

NMR-(CDCa): 5092(S), l .l l(S 2. l4(S),.3.63(S).

MassSpe c:M 348 1 The middle band afforded 24 mg (25% yield.) of 5B-inutes, and 7% Example 20:

Degradation of Thioketals 27/28 into SB-androstanl 7-one (3 l Similarlythe thioketal mixture 27/28 required degradation of the D-homo steroid(28) to provide a true steroid (3l This was accomplished by treatmentwith Raney nickel to remove the thioketal group followed by ozonolysisto produce the steroid (31), as follows:

a. Treatment with Raney nickel. Into a 25 ml roundbottom flask wasplaced 175 mg (0.426 mmole) of the thioketal 27/28 (containing 18% ofanother impurity), l5 ml of ethyl acetate, 5 ml of ethanol. and ca. 3 gof wet (water) Raney nickel. This mixture was stirred at roomtemperature for 4 hours (vpc showed all thioketal gone) filtered toremove Raney nickel and the nickel washed severaltimes with ethylacetate. The organic washings ,were washed with brine and dried overanhydrous sodium sulfate. Filtration and evaporation in vacuo afforded109 mg (7871 yield) of a clear oil. Nmr of this material showed somevinyl protons.

onto a siliea gel plate (20 cm X 20 cm X 0.1 cm) and.

b. Ozonolysis. The above materialwas dissolved in a mixture of 1 ml ofmethanol and 3 ml of ethyl acetate and the solution chilled to .78.Ozone was bubbled through the solution until a permanent blue color wasproduced. The solution was allowed to stand for 5 min utes andtoexcessozone was flushed from the solution with oxygen. Dimethyl sulfide (0.5ml) was then added at 78 with stirring and the solution stirred whilewarming to room temperature. After 30 minutes the solution wasconcentrated in vacuo to afford 140 mg of a yellow oil. This materialwas absorbed into a silica gel plate cm X 20 cm X01 cm) and eluted withethyl acetatezhexane (1:4) to afford 21 mg (24% yield) of5,8-androstan17-one (31 (R 0.5) as a clear oil. This material coinjected(3% XE-60, 220) with the authentic material and the infrared spectrawere similar."

Example 21:

hi a ml flask equipped with a magnetic stirring bar were placed 284 mg(0.95 mmolcs) of the enone (24). 1.60 ml of glacial acetic acid. 0.40 mlacetic anhydride and 6 ml of tetrachloroethylenc. The flask was placedin a 100 oil bath and the contents stirred. The oxidant solution wasprepared immediately before use by adding 1.60 ml glacial acetic acidand 0.40 ml acetic anhydride to 2.75 ml of tertiary butyl chromatereagent (2.4 M in tetrachloroethylene, 7.0 equivalents). The chromatereagent solution was prepared according to the procedure of Heusler andWetterstein (K. Huesler. A. Wetterstein, Helv. Chem. Acta 35. 384,(1952)) except that tetraehloroethylene was used rather than carbontetrachloride. The oxidant solution was added over a 5 minute period tothe stirred solution of the enone (24) at 100. After 55 minutes at 100the reaction vessel was allowed to cool and 5 ml of saturated aqueousoxalic acid was added. followed after 10 minutes by some solid oxalicacid. After another 10 minutes the reaction mixture was poured into aseparatory funnel and extracted with ether (3 X 15 ml). The combinedether layers were washed with water then worked up as usual. Evaporationof the solvent in vacuo left the crude enedione (37), 0.253 g as a paleyellow viscous oil. Vpc analysis of this crude product showed 89% of theintegrated area corresponded to the desired enedione (37). All of theabove product was dissolved in the minimum amount of hexane are reflux,then allowed to cool to 23. An oil came out of solution." On furthercooling to a white solid then a fluffy white product were precipitated.The supernatant was carefully removed by pipette. A total of 185 mg ofmaterial that was 95% pure by vpc was collected. The supernatant oncooling to 78 yielded more product 15 mg; total yield, 64% Tlc (silicagel, ethyl acetate/hexane l/l, R, 0.34) showed all the impuritiesremained in the 78 supernatant. A sample was purified by tlc (silica,ethyl acetate/hexane l/ 1) followed by recrystallization from hexane (2X that yielded white plates mp 127131. Concentration of the motherliquor caused very fine needles mp 137138 to crystallize. Bothcrystalline forms were the pure 17,8 isomer.

Analysis: Calcd for C H O C, 80.21; H, 9.62; found: C. 79.96; H. 9.59Spectral Data:

A-pregnen-3.20-dione UV: h 3" 230 My. (F 81.950.)

Example 22 A"*pregnadien-3.20-dione (38) In a 25 ml flask were placed0.180 g (0.572 mmoles) of A'-pregnen-3.20-dione (37) 0.196 g (1.5equivalents) of 2.3-dichloro-5 ,6-dicyano-benzoquinone. 0. 140 g benzoicacid (2.0 equivalents) and 9 ml dry tol uene. The flask was fitted witha condensor, degassed with nitrogen and placed in a 120 oil bath for 4hours. The reaction mixture was then poured into saturated NaHCQ, andextracted with ether (3X). The usual workup yielded 144 mg of brown oil.There was no trace of starting material by either tlc or 'vpc. Thedesired A" -pregnadien-3.20-di0ne (38) integrated to 8871 of the vaporphase chromatogram. A sample was purified by recrystallization fromethyl acetate/hexane (2/1) to give colorless plates imp 176.

Analysis: Calcd for C H O C. 80.73; H. 9.03; Found: C. 80.68; H. 8.73Spectral Data:

6.17 '(m) of A-ring) 7.35. 7.70. 11.00, 11.22

Example 23: Progestronc (39) lna 50 ml flask equipped with a stopcocksidearm and stirrer bar were placed 144 mg of crude diencdione (38) and30 mg Rh (P j 1 catalyst. The flask was thoroughly degassed withhydrogen before 7 ml of toluene/absolute ethanol 1/1, nitrogen degassed)was added via syringe. The flask was stirred under a positive pressureof hydrogenation. The resulting pale yellow orange solution was stirred8- hours. The flask was removed from the hydrogenation apparatus andstirred in air. After solvent removal, the residue was taken up in 5071ethyl acetate in hexane 'fthen filtered through a celite/glass woolplug. Evaporation of the. filtrate in vacuo left a pale brown oil.'ll8mg. Vpc analysis showed that 17% of the starting material was. not bydrogenated. In other experiments complete hydrogenation of the 1.2 bondhas been effected. The desired product was separated from the startingmaterial by Spectral Data:

NMR: (CDCIR) um s (s. 3H. 1x) 11x 1 3H m) 11: (s. in (-Zlb 5.7x (S. IH.(-41 IR: (KBr) 3.35 343x. 3.40 (cm 5.x? R ('nbmu 7.35 ms. we may n45This sumplcs nmr and ir spectra were identical to the spectra of bothnatural progesterone.

We claim:

1. Compounds of formula progesterone and wherein R". R and R arehydrogen or methyl; X is hydroxyl.

1. COMPOUNDS OF FORMULA